Fipronil-related heterocyclic compounds: Structure-activity relationships for interaction with gamma-aminobutyric acid- and voltage-gated ion channels and insecticidal action

To investigate the role of the heterocyclic moieties of nitrogen-containing phenyl heterocyclic compounds (PHCs) in interaction with gamma-aminobutyri c acid (GABA)-gated chloride channels, diverse classes of PHCs were examine d for their ability to inhibit the specific binding of [H-3]4'-ethynyl-4-n- propylbicycloorthobenzoate (EBOB), a noncompetitive GABA antagonist, to hou sefly head and rat brain membranes. PUCs that inhibited [H-3]EBOB binding i nclude pyrazoles: 1H-1,2,3-triazoles; a 1H-1,2,4-triazole; 1,3,4-oxadiazol- 2(3H)-ones; a 1,3,4-oxadiazole-2(3H)-thione; 1,2,4-oxadiazoles; a 1,2,4-thi adiazole; thiazoles; a 4(3H)-pyrimidinone: and a 2,4(1H,3H)-pyrimidinedione . An analogue (1) of the pyrazole insecticide fipronil, bearing an SCF3 gro up in place of the S(O)CF3, was found to be the most potent inhibitor wit I C(50)s of 7.55 and 177 nM in housefly head and mt brain membranes, respecti vely. 3-(2,6-Dichloro-3-trifluoromethylphenyl)-5-t-butyl-1,3,4-oxadiazol-2( 3H)-one exhibited the highest selectivity fur housefly GABA receptors versu s rat receptors (IC50 rat/IC50 fly >204). PHCs that exhibited a comparable selectivity include a pyrazole and a 1H-1,2,3-triazole interaction of 16 se lected PHCs with rat brain GABA-gated channels was also examined using [S-3 5]t-butylbicyclophosphorothionate (TBPS), a radioligand for the mammalian n oncompetitive antagonist site. A plot of pTC(50)s of 12 PHCs revealed a clo se correlation (r = 0.93) between their potency in inhibiting [H-3]EBOB and [S-35]TBPS binding. Scatchard analyses of the inhibition of [S-35]TBPS bin ding by 1 suggested a compeiiti\e-typr inhibition. A plot of the potency of IJ PHCs in inhibiting [H-3]EBOB binding to housefly head membranes against their piperonyl butoxide-synergized insecticidal effect on German cockroac hes yielded a close correlation (r = 0.89), with the exception of five tria zoles and a 2,4(1H,3H)-pyrimidinedione. Although several selected PHCs also inhibited the specific binding of [H-3]batrachotoxinin A 20-alpha-benzoate , a tritiated analogue of the sodium channel activator batrachotoxinin, to synaptosomes and membranes prepared from mouse brains, housefly heads, and American cockroach nerve cords, the concentrations required were higher tha n those of standard compounds producing significant effects on this system. The results demonstrate that a variety of five- and six-membered, nitrogen -containing heterocyclic compounds, bearing a 2,6-dichloro-4-trifluoromethy phenyl or 2,4,6-trichlorophenyl group, interact with ionotropic GABA recept ors. Several PHCs display higher affinities for housefly GABA receptors and high selectivity as compared to rat GABA receptors. PHCs' insecticidal act ivity is mediated by their interaction with GABA-gated chloride channels. ( C) 2000 Academic Press.